Platelet thromboxane inhibition by low-dose aspirin in polycythemia vera: Ex vivo and in vivo measurements and in silico simulation

Abstract

Low-dose aspirin is currently recommended for patients with polycythemia vera (PV), a myeloproliferative neoplasm with increased risk of arterial and venous thromboses. Based on aspirin pharmacodynamics in essential thrombocythemia, a twice-daily regimen is recommended for patients with PV deemed at particularly high thrombotic risk. We investigated the effects of low-dose aspirin on platelet cyclooxygenase activity and in vivo platelet activation in 49 patients with PV, as assessed by serum thromboxane (TX) B₂ and urinary TXA₂ /TXB₂ metabolite (TXM) measurements, respectively. A previously described pharmacokinetic-pharmacodynamic in silico model was used to simulate the degree of platelet TXA₂ inhibition by once-daily (q.d.) and twice-daily (b.i.d.) aspirin, and to predict the effect of missing an aspirin dose during q.d. and b.i.d. regimens. Serum TXB₂ averaged 8.2 (1.6-54.7) ng/ml and significantly correlated with the platelet count (γ = 0.39) and urinary TXM (γ = 0.52) in multivariable analysis. One-third of aspirin-treated patients with PV displayed less-than-maximal platelet TXB₂ inhibition, and were characterized by significantly higher platelet counts and platelet-count corrected serum TXB₂ than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB₂ and urinary TXM values. The in silico model predicted complete inhibition of platelet-derived TXB₂ by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB₂ value while on aspirin q.d. and treated short-term with a b.i.d. regimen. In conclusion, one in three patients with PV on low-dose aspirin display less-than-maximal inhibition of platelet TXA₂ production. Serum TXB₂ measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV.